Isolated SMN2 gene deletion: Novel mutation presenting as late onset spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder predominantly caused by mutations or deletions in the SMN1 gene, leading to progressive motor neuron degeneration. The SMN2 gene, a paralog of SMN1 , modulates disease severity but is typically not considered pathogenic in isolation. Here, we report a rare case of a 6-year-old boy born to a third-degree consanguineous couple, presenting with delayed motor milestones, progressive lower limb weakness, hypotonia, and tongue fasciculations. Despite a normal SMN1 gene, deletion/duplication analysis (multiplex ligation-dependent probe amplification) revealed a heterozygous deletion of exons 7 and 8 in the SMN2 gene, classified as a variant of uncertain significance. Over a 3-year follow-up, the child’s progressive motor decline paralleled the natural course of classical SMA. This case challenges the current literature that isolated SMN2 mutations lack clinical significance. The progressive phenotype suggests possible pathogenicity of certain SMN2 variants, emphasizing the need for integrated clinical-genetic assessment, especially in atypical presentations. Isolated SMN2 gene deletions may contribute to clinically significant neuromuscular disease. Early identification, vigilant monitoring, and comprehensive genetic counseling are vital in such scenarios.